The role of IL-2 as a neuromodulator and trophic factor in the brain has been the focus of much research. IL- 2 has been implicated in the pathogenesis of multiple sclerosis and several major neuropsychiatric disorders including Alzheimer's disease, schizophrenia, and Parkinson's disease. IL-2 is an immunoregulatory cytokine that is indispensable for maintaining immunological homeostasis. IL-2 is also expressed by brain cells, and exerts potent effects on acetylcholine release from septohippocampal cholinergic neurons and trophic effects on fetal septal and hippocampal neurons. Our lab has previously cloned and sequenced the IL-2 heterotrimeric receptor complex in brain, and shown that IL-2 receptors are enriched in the hippocampus and related limbic regions. Using IL-2 knockout mice, we have found that IL-2 gene deletion results in septohippocampal pathology in adult mice. Our data and the literature suggest that these alterations are due to both the loss of IL-2's trophic effects on neurons, and to unique characteristics of autoimmunity caused by IL-2 deficiency in the peripheral immune system. The proposed studies are designed to disentangle which components of the septal and hippocampal neuropathology are due to the absence of IL-2 in the brain versus peripheral immune cells. Our working hypotheses that we will test are that the loss of medial septal neurons that we have observed in IL-2 knockout mice is due principally to autoimmunity, whereas the hippocampal pathology is due the loss of the neurotrophic actions of brain IL-2. These and other important objectives will be achieved by successful completion of the following Specific Aims. The experiments proposed in Aim 1 will assess the development of: 1) peripheral autoimmunity, 2) the neuroimmunological status of the septum and hippocampus, and 3) septal and hippocampal neuropathology in IL-2 knockout mice. Aims 2 and 3 will use a combination of novel congenic mice and adoptive transfer manipulations to test our working hypotheses. The research proposed in Aim 2 will test the hypothesis that loss of medial septal neurons results from peripheral IL-2 deficiency-induced autoimmunity. Experiments proposed in Aim 3 will test the hypothesis that brain IL-2 is essential for the normal development and survival of neurons in the dentate gyrus. Learning and memory will also be tested in Aims 2 and 3 to determine the functional significance of the neuropathology. These studies will provide essential new insight into brain IL-2's intrinsic actions in the septohippocampal system. This unique mouse model will also provide much needed new data elucidating neuroimmunological and autoimmune processes involved in brain development and disease. Such information may ultimately provide critical new insight into the role of brain cytokines and autoimmunity in prominent neurological and neuropsychiatric diseases (e.g., multiple sclerosis, Alzheimer's disease, schizophrenia).